When blood is coagulated, the water soluble protein fibrinogen is converted to an insoluble gel of aggregated fibrin molecules. This gel, which is mechanically weak, is easily broken down by proteolytic enzymes. In the presence of Factor XIII (fibrinoligase), as in normal blood and plasma, the fibrin gel is converted to crosslinked, insoluble and mechanically stable fibrin, which is considerably more resistant to proteolytic enzymes than the fibrin gel. If Factor XIII activity is inhibited, the fibrin remains in its non-crosslinked, easily dissolvable form, and in this manner the formation of thrombosis is counteracted. Physiologically acceptable inhibitors of Factor XIII are therefore of great therapeutical interest.
It is known that certain compounds containing a primary amino group and an aryl group can act as competitive inhibitors of Factor XIII; see e.g. L. Lorand & L. G. Nilsson, Molecular Approach for Designing Inhibitors to Enzymes Involved in Blood Clotting in Drug. Design, Vol. 3, E. J. Arens, editor, Academic Press, N. Y. 1972. One example of this type of compound is danslylcadaverine, having the following structure: ##STR3##
Dansylcadaverine and the corresponding analogue having a 3-thiapentane side chain have proved to be rather active. It is, however, also known that naphthylamines can be highly carcenogenic, and it is not advisable to use naphthylamino compounds as drugs, especially drugs being administered for a long period of time. Great efforts have been made to find alternative, toxicologically acceptable compounds having the same or better activity than these naphthalene derivatives, but so far without success. It should be noticed in this connection that corresponding compounds containing an optionally substituted benzene ring, instead of the napthalene ring, have been tested and found to present such low activities that they were considered to be of no therapeutic interest.
It has now surprisingly been found that compounds of formula (I) below, containing a diorthosubstituted benzene ring, are considerably more active than the known benzene derivatives, while at the same time are more acceptable from the toxicological viewpoint, than to the above mentioned naphthylamine derivatives.